Abstract
Cue-elicited drug-craving is a cardinal feature of addiction that intensifies (incubates) during protracted withdrawal. In a rat model, these addiction-related behavioral pathologies are mediated, respectively, by time-dependent increases in PI3K/Akt1 signaling and reduced Group 1 metabotropic glutamate receptor (mGlu) expression, within the ventromedial prefrontal cortex (vmPFC). Herein, we examined the capacity of single oral dosing with everolimus, an FDA-approved inhibitor of the PI3K/Akt effector mTOR, to reduce incubated cocaine-craving and reverse incubation-associated changes in vmPFC kinase activity and mGlu expression. Rats were trained to lever-press for intravenous infusions of cocaine or delivery of sucrose pellets and then subjected to tests for cue-reinforced responding during early (3 days) or late (30–46 days) withdrawal. Rats were gavage-infused with everolimus (0–1.0 mg/kg), either prior to testing to examine for effects upon reinforcer-seeking behavior, or immediately following testing to probe effects upon the consolidation of extinction learning. Single oral dosing with everolimus dose-dependently blocked cocaine-seeking during late withdrawal and the effect lasted at least 24 h. No everolimus effects were observed for cue-elicited sucrose-seeking or cocaine-seeking in early withdrawal. In addition, everolimus treatment, following initial cue-testing, reduced subsequent cue hyper-responsivity exhibited observed during late withdrawal, arguing a facilitation of extinction memory consolidation. everolimus’ “anti-incubation” effect was associated with a reversal of withdrawal-induced changes in indices of PI3K/Akt1/mTOR activity, as well as Homer protein and mGlu1/5 expression, within the prelimbic (PL) subregion of the prefrontal cortex. Our results indicate mTOR inhibition as a viable strategy for interrupting heightened cocaine-craving and facilitating addiction recovery during protracted withdrawal.
Highlights
Drug-craving is a cardinal feature of addiction that can be elicited by re-exposure to drug-associated cues
At withdrawal day 30 (WD30)–46 from cocaine selfadministration, rats were pretreated with VEH or a range of everolimus doses (0.01, 0.1, and 1.0 mg/kg) at 30 min prior to testing (Cue Test 1)
Everolimus pre treatment decreases cocaine-seeking only following incubation Following 10 days of cocaine self-administration (6 h on day 1; 2 h on days 2–10), rats were pretreated with VEH or 1.0 mg/kg everolimus (E1.0) prior to a cue-elicited cocaine-seeking test on either withdrawal day 3 (WD3) or WD30
Summary
Drug-craving is a cardinal feature of addiction that can be elicited by re-exposure to drug-associated cues. Of potential relevance to anti-craving medications development, there exists a number of FDA-approved, orally bioavailable, medications that inhibit the PI3K/Akt1/mTOR signaling pathway (c.f., [22, 23]) This fact led us to examine the effects of acute, oral, pretreatment with the FDA-approved and commercially available allosteric mTOR inhibitor everolimus (formerly RAD 001; a.k.a., Zortress, Certican, Afinitor, Votubia, Evertor) upon the incubation of cue-elicited cocaine-craving in a rat model of addiction and its relation to the activational state of PI3K/Akt1/mTOR signaling within vmPFC subregions. Our results show that acute, oral, pretreatment with everolimus blocks incubated cocaine-craving in rats over days and reverses incubation-related protein adaptations within vmPFC subregions Such findings demonstrate the therapeutic potential of systemic treatment with current FDA-approved PI3K/Akt1/mTOR inhibitors for reversing vmPFC neuroadaptations driving perseverative cocaine-craving
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